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Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.

Artikel i vetenskaplig tidskrift
Författare Mats Hellström
Li-Kun Phng
Jennifer J Hofmann
Elisabet Wallgard
Leigh Coultas
Per Lindblom
Jackelyn Alva
Ann-Katrin Nilsson
Linda Karlsson
Nicholas Gaiano
Keejung Yoon
Janet Rossant
M Luisa Iruela-Arispe
Mattias Kalén
Holger Gerhardt
Christer Betsholtz
Publicerad i Nature
Volym 445
Nummer/häfte 7129
Sidor 776-80
ISSN 1476-4687
Publiceringsår 2007
Publicerad vid Institutionen för neurovetenskap och fysiologi
Sidor 776-80
Språk en
Länkar dx.doi.org/10.1038/nature05571
Ämnesord Amyloid Precursor Protein Secretases, antagonists & inhibitors, metabolism, Animals, Endothelium, Vascular, cytology, metabolism, Membrane Proteins, deficiency, metabolism, Mice, Neovascularization, Physiologic, drug effects, physiology, Receptor, Notch1, deficiency, metabolism, Retina, cytology, metabolism, Signal Transduction, drug effects
Ämneskategorier Cell- och molekylärbiologi, Cellbiologi, Morfologi

Sammanfattning

In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.

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